Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis
Nadine Nagy, … , Thomas N. Wight, Paul L. Bollyky
Nadine Nagy, … , Thomas N. Wight, Paul L. Bollyky
Published October 1, 2015; First published September 14, 2015
Citation Information: J Clin Invest. 2015;125(10):3928-3940. https://doi.org/10.1172/JCI79271.
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Research Article Immunology

Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis

Abstract

We recently reported that abundant deposits of the extracellular matrix polysaccharide hyaluronan (HA) are characteristic of autoimmune insulitis in patients with type 1 diabetes (T1D), but the relevance of these deposits to disease was unclear. Here, we have demonstrated that HA is critical for the pathogenesis of autoimmune diabetes. Using the DO11.10xRIPmOVA mouse model of T1D, we determined that HA deposits are temporally and anatomically associated with the development of insulitis. Moreover, treatment with an inhibitor of HA synthesis, 4-methylumbelliferone (4-MU), halted progression to diabetes even after the onset of insulitis. Similar effects were seen in the NOD mouse model, and in these mice, 1 week of treatment was sufficient to prevent subsequent diabetes. 4-MU reduced HA accumulation, constrained effector T cells to nondestructive insulitis, and increased numbers of intraislet FOXP3+ Tregs. Consistent with the observed effects of 4-MU treatment, Treg differentiation was inhibited by HA and anti-CD44 antibodies and rescued by 4-MU in an ERK1/2-dependent manner. These data may explain how peripheral immune tolerance is impaired in tissues under autoimmune attack, including islets in T1D. We propose that 4-MU, already an approved drug used to treat biliary spasm, could be repurposed to prevent, and possibly treat, T1D in at-risk individuals.

Authors

Nadine Nagy, Gernot Kaber, Pamela Y. Johnson, John A. Gebe, Anton Preisinger, Ben A. Falk, Vivekananda G. Sunkari, Michel D. Gooden, Robert B. Vernon, Marika Bogdani, Hedwich F. Kuipers, Anthony J. Day, Daniel J. Campbell, Thomas N. Wight, Paul L. Bollyky

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Figure 5

4-MU treatment prevents progression of insulitis but does not cure established diabetes.

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4-MU treatment prevents progression of insulitis but does not cure estab...
(A) Blood glucose of DORmO and control mice started on 4-MU at 8 weeks of age, taken off 4-MU between 15 and 18 weeks of age, and restarted on 4-MU thereafter (n = 10). (B) Blood glucose of DORmO and BALB/c (control) mice fed 4-MU chow, beginning at 12 weeks of age (n = 10). (C) Blood glucose following IPGTT for control chow–fed BALB/c and DORmO mice at 10 weeks of age (n = 8 mice per group). (D) Blood glucose following IPGTT of DORmO mice from C treated for 2 weeks with 4-MU or control chow. (E) Blood glucose following IPGTT of BALB/c and DORmO mice at 10 weeks of age following 4-MU treatment for 2 weeks (n = 6). (F) Blood glucose following IPGTT for the same mice as in E, now made hyperglycemic by STZ treatment (n = 6). Data represent mean ± SEM.